CN102304047A - Gamma-hydroxy olic acid ester derivatives and use thereof in preparation of antitumor medicines - Google Patents
Gamma-hydroxy olic acid ester derivatives and use thereof in preparation of antitumor medicines Download PDFInfo
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Abstract
The invention discloses gamma-hydroxy olic acid ester derivatives having antitumor activity and the use thereof in the preparation of antitumor medicines, and belongs to the field of biochemical technology. The structure of the gamma-hydroxy olic acid ester derivatives is shown below. The results of classic methyl thiazolyl tetrazolium (MTT) tumor cell medicine screening experiments, AnnexinV/PI double-staining cell apoptosis measurement experiments, cell periodical detection experiments and in-vivo antitumor experiments prove that the gamma-hydroxy olic acid ester derivatives have proliferation inhibition effects on breast cancer, bladder cancer and liver cancer and can be used in the preparation of antitumor medicines as an active ingredient.
Description
Technical field
The invention belongs to the biochemical technology field, relate to a kind of γ-hydroxy-acetylenic acid ester derivative; The present invention also relates to the application of γ-hydroxy-acetylenic acid ester derivative in the preparation antitumor drug simultaneously.
Background technology
Cancer has become the main killer who threatens the human life healthy.It is reported that global cancer morbidity is rapid ascendant trend, will increase by 50% in the following more than ten years.China nearly two cancer morbidity during the last ten years increases closely 70%, and mortality ratio increases nearly 30%.Along with vitochemical develop rapidly, chemotherapy has become one of field with fastest developing speed in the oncotherapy.It is not only the supplementary means of oncotherapy, and has developed into one of the most general, effective means and means gradually.Thereby separation, design with potential active compound for anti tumor are synthetic and transformation will provide indispensable basis for chemotherapy.
Discover that the propynol structure is a chiral building block important in many natural products and the drug molecule.This compounds extensively exists in terrestrial plant and the ocean raw foam body class organism; In recent years the researchist also finds in the secondary metabolite of all kinds of fungies, also to contain this class formation, and 1000 kinds of compounds that comprise this structure of surpassing are arranged in the natural product of having reported at present.It is active that this compounds shows widely multi-biological, cytotoxicity for example, and antibiotic and sterilizing is active, and is anticancer antitumor, HIV-resistant activity, plurality of enzymes restraining effect etc.Though several types of important cancer therapy drugs are (like Calicheamycin; C-1027; Esperamicin; Maduropeptin) and AIDS medicine (like Efavirenz) also contain this structure, but the big limitations of development of method of asymmetric synthesis people to the structure activity study of this compounds and contain the initiative of this class formation new drug.
Below be separating obtained several types of primary structure unit that contain in the alkynes natural product in the natural product:
Wherein A, B, three types of chiral propargylic alcohol structures of C are the most general, contain alkynes lipid acid D, the E compounds takes second place, and F is then comparatively rare for the relatively poor γ of Separation of Natural Products conditional stability-hydroxypropyn acid structure, but performance has biological activity preferably.This shows that propynol structure and undersaturated fatty acid structure are the active important structure building blocks of this compounds performance multi-biological.
Thereby structure is comparatively rare but have the γ of better anti-tumor activity-hydroxypropyn acid structure will become the important as precursors of development new type antineoplastic medicine in the natural product.But owing to lack the method for asymmetric synthesis of ripe practical γ-hydroxypropyn acid before this, thereby cause failing the anti-tumor activity research of system that this compounds is done.This class formation also is synthetic very important structure building block and the synthetic intermediate of other biologically active compounds in addition.Though the asymmetric synthesis of chiral propargylic alcohol is obtaining development at full speed over past ten years; But the development of this type of method of asymmetric synthesis only limits to the structure of A, B, C class simple structure, and the asymmetric synthesis of γ-hydroxypropyn acid (F) has received great limitation because of its active constructional feature.Be directed to this, developed the method for asymmetric synthesis of simple and easy to do all kinds of chiral propargylic alcohol structures, the method for asymmetric synthesis of chirality γ-hydroxypropyn acid esters especially and successfully is applied to-serial important biomolecule active compound asymmetric complete synthesis.
Summary of the invention
The object of the present invention is to provide provides a kind of γ-hydroxy-acetylenic acid ester derivative with anti-tumor activity.
Another object of the present invention provides the application of a kind of γ-hydroxy-acetylenic acid ester derivative in the preparation antitumor drug.
One, γ-hydroxy-acetylenic acid ester derivative
γ of the present invention-hydroxy-acetylenic acid ester derivative, its structural formula is following:
R
1Be Wasserstoffatoms, (C1～C6)-alkyl, halogen atom substituted (C1～C6)-alkyl, (C1～C6)-alkoxyl group, preferred methoxyl group, halogen atom substituted (C1～C6)-alkoxyl group, amino, single (C1～C6)-alkylamino, two-N, N-(C1～C6)-alkylamino.
R
2Be phenyl, substituted phenyl, naphthyl, substituted naphthyl, assorted aromatic base, (the saturated fatty base of C1～C20), (the unsaturated fatty acids base of C1～C20), (C2～C20)-alkenyl, (C2～C20)-alkynyl group.
The structural formula of said substituted phenyl is following:
R wherein
3, R
4, R
5, R
6, R
7For independent of each other be Wasserstoffatoms, halogen, cyanic acid, nitro, (C1～C6)-alkyl; At least one halogen atom substituted (C1～C6)-alkyl, (C1～C6)-alkoxyl group, at least one halogen atom substituted (C1～C6)-alkoxyl group, (C2～C6)-alkenyl; (C2～C6)-alkynyl group, (C3～C8)-naphthenic base, (C1～C6)-alkoxyl group carbonyl oxygen base, (C1～C6)-alkyl carbonyl oxy; (C1～C4)-alkylthio, (C1～C4)-the alkyl sulfinyl, (C1～C4)-alkyl sulphonyl, (C1～C6)-alkoxyl group-(C1～C6)-alkyl; Amino, single (C1～C6)-alkylamino, two-N, N-(C1～C6)-alkylamino.R wherein
3And R
6Preferred halogen, trifluoromethyl, during trifluoromethoxy, R
4, R
5, R
7Preferred Wasserstoffatoms.
X is a Sauerstoffatom, sulphur atom, NH, disubstituted hydroxyl on identical C atom.
Two, γ-hydroxy-acetylenic acid ester derivative is synthetic
1, the compound method of chirality (R)-γ-hydroxy-acetylenic acid ester (referring to Org.Lett.2007,9,2329-2332): under argon shield, containing chiral ligand ((S)-2-(4-Methyl benzenesulfonyl amino)-1; 1-phenylbenzene-3-phenyl-1-propyl alcohol, 21.6mg, 0.06mmol; In toluene 30mol%) (2.4mL) solution, disposable adding glycol dimethyl ether (20.7 μ L, 02mmol; 100mol%), zinc ethyl solution (0.6mL, 0.6mmol, 300mol%) with propynoic acid methyl esters (53.5 μ L; 0.2mmol, 300mol%), in 25 ℃ of following restir 7 hours; Solution gradually becomes brown, adds Ti (OiPr) then
4(30mol%), stirring adds 0.2mmol aldehyde after half a hour, finishes (TLC detection) until reaction for 17.5 μ L, 0.06mmol.Use saturated NH
4The reaction of going out of Cl aqueous solution collection, with dichloromethane extraction three times, the merging organic phase is used the saturated common salt water washing, anhydrous Na
2SO
4Drying is evaporated to dried.The oily matter that obtains is through purified (silicagel column, sherwood oil: ETHYLE ACETATE=9: 1).
2, the compound method of chirality (S)-γ-hydroxy-acetylenic acid ester (referring to Angew.Chem., Int.Ed.2005,45; 122-125.): under argon shield, containing chiral ligand (R)-dinaphthol (28.6mg, 0.10mmol; In methylene dichloride 40mol%) (3mL) solution, add hexamethylphosphoramide (85 μ L, 1.0mmol successively; 200mol%), the zinc ethyl solution of 1M (1mL, 1.0mmol is 400mol%) with propynoic acid methyl esters (85 μ L; 1.0mmol, 400mol%), under room temperature, stirred 16 hours; Solution gradually becomes brown, and (74 μ L, 0.25mmol 100mol%), stir adding 0.25mmol aldehyde after 1 hour, finish (TLC detection) until reaction to add Ti (OiPr) 4 then.Use saturated NH
4The reaction of going out of Cl aqueous solution collection, with dichloromethane extraction three times, the merging organic phase is used the saturated common salt water washing, anhydrous Na
2SO
4Drying is evaporated to dried.The oily matter that obtains is through purified (silicagel column, sherwood oil: ETHYLE ACETATE=9: 1).The structural formula of said aldehyde is following:
R
2Be phenyl, substituted phenyl, naphthyl, substituted naphthyl, assorted aromatic base, (the saturated fatty base of C1～C20), (the unsaturated fatty acids base of C1～C20), (C2～C20)-alkenyl, (C2～C20)-alkynyl group.
The structural formula of said substituted phenyl is following:
R wherein
3, R
4, R
5, R
6, R
7For independent of each other be Wasserstoffatoms, halogen, cyanic acid, nitro, (C1～C6)-alkyl; At least one halogen atom substituted (C1～C6)-alkyl, (C1～C6)-alkoxyl group, at least one halogen atom substituted (C1～C6)-alkoxyl group, (C2～C6)-alkenyl; (C2～C6)-alkynyl group, (C3～C8)-naphthenic base, (C1～C6)-alkoxyl group carbonyl oxygen base, (C1～C6)-alkyl carbonyl oxy; (C1～C4)-alkylthio, (C1～C4)-the alkyl sulfinyl, (C1～C4)-alkyl sulphonyl, (C1～C6)-alkoxyl group-(C1～C6)-alkyl; Amino, single (C1～C6)-alkylamino ,-N, N-(C1～C6)-alkylamino.R wherein
3And R
6Preferred halogen, trifluoromethyl, during trifluoromethoxy, R
4, R
5, R
7Preferred Wasserstoffatoms.
Three, the antitumour activity of γ-hydroxy-acetylenic acid ester derivative experiment
Tumour cell EJ (bladder cancer) is available from Wuhan China typical culture collection center, with adding 10% calf serum, penicillium mould (100U/ml), Streptomycin sulphate (100 μ g/ml), NaHCO
3RPMI RPMI-1640 (2-0mg/ml) is at 37 ℃, 5%CO
2Conventional cultivation under the condition, the cell experiment in vegetative period of taking the logarithm.
1, MTT tumour cell medicament screening experiment
Experimental technique: the MTT full name is that (z-y1)-3,5-di-phenytetrazoliumromide is a kind of dyestuff of yellow color to 3-(4,5)-dimethylthiahiazo.In the viable cell plastosome succinodehydrogenase can metabolism reduction MTT, simultaneously under the effect of Lrax, (what of Formazan) ， Jia Za can be measured at the 570nm place with ELIASA to generate blue (or bluish voilet) water-fast Jia Za.Under normal conditions, first Za growing amount is directly proportional with viable count, therefore can infer the number that viable cell according to optical density(OD) OD value.Owing to do not contain succinodehydrogenase in the dead cell, therefore add MTT and can not respond.The cancer cells of exponential growth, after 0.25% tryptic digestion with the configuration of D-Hanks damping fluid, piping and druming makes it to become single cell suspension.It is 5 * 104/ml that counting makes cell concn, and 90 μ l enchylema join in 96 orifice plates, places and spends the night 24 hours, adds the medicine of 10 μ l different concns then, parallel six holes of every concentration.After cultivating 48 hours more jointly, every hole adds the MTT (5mg/ml) of 10 μ l, and in 37 ℃ of incubators, cultivates altogether 4 hours.Then nutrient solution is discarded, every hole adds 150 μ l DMSO and comes Rong Xie Jia Za.Tissue Culture Plate is shaken Shi Jia Za dissolve fully on the micropore oscillator, and then measure the light absorption value at 490nm place on Bio-Rad 680 ELIASAs.Each concentration repeats 6 holes in the experiment, and each experiment repeats 3 times at least.Test the drug effect of different concns respectively, the result representes with IC50.
Experimental result: show that γ of the present invention-hydroxy-acetylenic acid ester derivative all has inhibition proliferation function (table 3 and table 4) for tumour cell, all shows the restraining effect of cancer cells about 10 μ M.Wherein aromatics obviously shows better activity than aliphatics, meanwhile, ortho position, contraposition contain halogen especially the substituted compound of fluorine also show better tumor suppression proliferation function.
2, the two mensuration apoptosis that dye of Annexin V/PI
Experimental technique: after using 1 * 106EJ cell cultures 24h, add the medicine of different concns, cultivate 48 hours more jointly after, tryptic digestion suspension cell centrifugal (the centrifugal 5min of 2000rpm) is collected, with PBS washed cell secondary (the centrifugal 5min of 2000rpm).The Binding Buffer suspension cell that adds 500 μ l then adds 5 μ l Annexin V/FITC mixings again, adds 5 μ l Propidium Iodide mixings at last.Cell is placed room temperature, lucifuge environment, reaction 5～15min, (BECKMAN-Coulter USA) detects to use Epics XL-4 flow cytometer.
Experimental result: choosing representational compound L S-11 is example, and its result shows like Fig. 1～4.Confirm further that by the result effect of medicine is to make cell generation apoptosis, along with the increase apoptosis number of time is also increasing, the apoptosis number increases late period after 48 hours, and the dead cell number also increases.This explanation is under the effect of physiological concentration, and medicine is to be directly proportional with the length of time for the influence of apoptotic degree, and under the effect of whole serum, not degraded of medicine, but lasting playing a role.And a large amount of Annexin V/PI pair is dyed the experiment of mensuration apoptosis and shows that the exercising result of all γ-hydroxy-acetylenic acid ester derivative is similar basically.
3, the cell cycle is detected
Experimental technique: use 1 * 10
6Behind the EJ cell cultures 24h, add the medicine of different concns, cultivate 48 hours more jointly after; Tryptic digestion suspension cell centrifugal (the centrifugal 5min of 2000rpm) is collected; PBS washed cell secondary (the centrifugal 5min of 2000rpm) with precooling adds precooling 70% ethanol, then in 4 ℃ of fixed overnight.Second day centrifugal collecting cell washed cell once with the PBS of 1mL, adds 500uLPBS and contains 50ug/mL ethidium bromide (PI); 100ug/mL RNaseA, 02%Triton X-100 is after 4 ℃ of lucifuges are hatched 30 minutes; (BECKMAN-Coulter USA) detects to use Epics XL-4 flow cytometer.
Experimental result: choosing representational compound L S-11 is example, and its result shows like Fig. 5～9.The presentation of results of cell cycle: compare with contrast, cell explains that medicine suppresses tumor proliferation through replicative phase that acts on DNA and the phase of transcribing because the effect of medicine is arrested in S phase and G2 phase in a large number.And a large amount of cell cycles is detected and shows that the exercising result of all γ-hydroxy-acetylenic acid ester derivative is similar basically.
4, anti-tumor in vivo experiment
Experimental technique: use mice transplanted tumor S180, available from tumour hospital, the mouse of use is the female mouse of cleaning level, and body weight 18～22g is bought by medical college of Lanzhou University experimentation on animals center.The S180 sarcoma is seeded in female mouse oxter with 107 every mouse 0.2ml.Carry out intraperitoneal administration at random in second day the mouse that has inoculated S180, dosage is 0.2ml again, and be administered once every day, continuous 11 days.Drug withdrawal disconnected vertebra next day is put to death, and weighs, and dissects and peels off the subcutaneous tumors body, claims that knurl is heavy.Be calculated as follows tumour inhibiting rate: tumour inhibiting rate (%)=(the average knurl of the average knurl weight-administration of control group group is heavy)/average knurl of control group heavy * 100%.
Experimental result: the result who chooses representational compound L S-11 (see figure 10) and LS-45 (seeing Figure 11) shows respectively: compound L S-11 and LS-45 can dose-dependently reduce tumor size under isolated condition; Suppress growth of tumor; And metering toxicity is lower below 25mg, for the not influence of life prolongation of mouse.And a large amount of anti-tumor in vivo experiments show that the exercising result of all γ-hydroxy-acetylenic acid ester derivative is similar basically.
Description of drawings
Fig. 1 is: two the dying of Annexin V/PI do not used the pharmaceutically-active EJ cell of LS-11;
Fig. 2 is the two EJ cells that dye 10 μ M LS-11 drug effect 12h of Annexin V/PI;
Fig. 3 is the two EJ cells that dye 10 μ M LS-11 drug effect 24h of Annexin V/PI;
Fig. 4 is the two EJ cells that dye 10 μ M LS-11 drug effect 48h of Annexin V/PI;
Fig. 5 does not use pharmaceutically-active EJ cell for PI singly dyes;
Fig. 6 singly dyes the EJ cell of 10 μ M LS-11 drug effect 24h for PI;
Fig. 7 singly dyes the EJ cell of 10 μ M LS-11 drug effect 48h for PI;
Fig. 8 singly dyes the EJ cell of 10 μ M LS-45 drug effect 24h for PI;
Fig. 9 singly dyes the EJ cell of 10 μ M LS-45 drug effect 48h for PI;
Figure 10 is the anti-tumor in vivo experimental result of compound L S-11;
Figure 11 is the anti-tumor in vivo experimental result of compound L S-45.
Embodiment
Through specific embodiment the structure of γ of the present invention-hydroxy-acetylenic acid ester derivative, the synthetic anti-tumor activity that reaches are done detailed explanation below.
Among the embodiment 1～43, the structure of γ-hydroxy-acetylenic acid ester derivative is following:
Its compound method can be selected the compound method of aforementioned chirality (R)-γ-hydroxy-acetylenic acid ester and the compound method of chirality (S)-γ-hydroxy-acetylenic acid ester for use according to different configurations, and according to different compounds, in building-up process, notes selecting for use corresponding aldehyde.Among the embodiment 1～43, characteristics such as the configuration of γ-hydroxy-acetylenic acid ester derivative, sign are seen table 1.
Table 1.
Among the embodiment 44～60, the structure of γ-hydroxy-acetylenic acid ester derivative is following:
Its compound method is seen before and is stated the compound method of chirality (R)-γ-hydroxy-acetylenic acid ester, and according to different compounds, in building-up process, notes selecting for use corresponding aldehyde.Among the embodiment 44～60, characteristics such as the configuration of γ-hydroxy-acetylenic acid ester derivative, sign are seen table 2.
Table 2.
Embodiment 61～98 all has the experimental result that suppresses proliferation function for γ-hydroxy-acetylenic acid ester derivative LS-1～LS-38 for tumour cell.The corresponding IC of each embodiment
50Value is seen table 3.
The corresponding IC of each embodiment of table 3.
50Value
Embodiment 99～114 all has the experimental result that suppresses proliferation function for γ-hydroxy-acetylenic acid ester derivative LS-40～LS-55 for tumour cell.The corresponding IC of each embodiment
50Value is seen table 4.
The corresponding IC of each embodiment of table 4.
50Value.
Claims (8)
1. γ-hydroxy-acetylenic acid ester derivative, its structural formula is following:
R
1Be Wasserstoffatoms, (C1 ~ C6)-alkyl, halogen atom substituted (C1 ~ C6)-alkyl, (C1 ~ C6)-alkoxyl group, halogen atom substituted (C1 ~ C6)-alkoxyl group, amino, single (C1 ~ C6)-alkylamino, two-N, N-(C1 ~ C6)-alkylamino;
R
2Be phenyl, substituted phenyl, naphthyl, substituted naphthyl, assorted aromatic base, (the saturated fatty base of C1 ~ C20), (the unsaturated fatty acids base of C1 ~ C20), (C2 ~ C20)-alkenyl, (C2 ~ C20)-alkynyl group;
X is a Sauerstoffatom, sulphur atom, NH, disubstituted hydroxyl on identical C atom.
2. γ-hydroxy-acetylenic acid ester derivative according to claim 1, it is characterized in that: the structural formula of said substituted phenyl is following:
R wherein
3, R
4, R
5, R
6, R
7For independent of each other be Wasserstoffatoms, halogen, cyanic acid, nitro, (C1 ~ C6)-alkyl; At least one halogen atom substituted (C1 ~ C6)-alkyl, (C1 ~ C6)-alkoxyl group, at least one halogen atom substituted (C1 ~ C6)-alkoxyl group, (C2 ~ C6)-alkenyl; (C2 ~ C6)-alkynyl group, (C3 ~ C8)-naphthenic base, (C1 ~ C6)-alkoxyl group carbonyl oxygen base, (C1 ~ C6)-alkyl carbonyl oxy; (C1 ~ C4)-alkylthio, (C1 ~ C4)-the alkyl sulfinyl, (C1 ~ C4)-alkyl sulphonyl, (C1 ~ C6)-alkoxyl group-(C1 ~ C6)-alkyl; Amino, single (C1 ~ C6)-alkylamino, two-N, N-(C1 ~ C6)-alkylamino.
According to claim 1 γ-hydroxy-acetylenic acid ester derivative as active substance in the application of preparation in the antitumor drug.
Like the said γ of claim 3-hydroxy-acetylenic acid ester derivative as active substance in the application of preparation in the antitumor drug, it is characterized in that: be used to prepare the anti-bladder cancer medicine.
Like the said γ of claim 3-hydroxy-acetylenic acid ester derivative as active substance in the application of preparation in the antitumor drug, it is characterized in that: be used to prepare medicines resistant to liver cancer.
Like the said γ of claim 3-hydroxy-acetylenic acid ester derivative as active substance in the application of preparation in the antitumor drug, it is characterized in that: be used to prepare anti-breast cancer medicines.
Like the said γ of claim 3-hydroxy-acetylenic acid ester derivative as active substance in the application of preparation in the antitumor drug, it is characterized in that: be used to prepare anti-prostate cancer medicine.
Like the said γ of claim 3-hydroxy-acetylenic acid ester derivative as active substance in the application of preparation in the antitumor drug, it is characterized in that: be used to prepare antileukemie medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104634768A (en) * | 2013-11-08 | 2015-05-20 | 中国农业科学院蔬菜花卉研究所 | Plant pathogen activity evaluation and bactericide high throughput screening method and kit |
| CN109704926A (en) * | 2019-01-29 | 2019-05-03 | 南京工业大学 | Anticancer activity molecular skeleton 1,4- enyne compounds and the preparation method and application thereof |
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2011
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104634768A (en) * | 2013-11-08 | 2015-05-20 | 中国农业科学院蔬菜花卉研究所 | Plant pathogen activity evaluation and bactericide high throughput screening method and kit |
| CN109704926A (en) * | 2019-01-29 | 2019-05-03 | 南京工业大学 | Anticancer activity molecular skeleton 1,4- enyne compounds and the preparation method and application thereof |
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